It is planned to continue our research in the area of thiazolo(5,4- d)pyrimidines, oxazolo(5,4-d)pyrimidines and the nucleosides of these and certain closely related heterocycles. It is planned to vary the exocyclic substituents at positions 2,5 and 7 as well as the site of glycosidation between positions 4 and 6 where the carbohydrate moiety will reside at a nitrogen in the pyrimidine moiety. The synthesis of nucleosides which are closely related, e.g., thieno(2,3-d)pyrimidine and furo(2,3-d)pyrimidine nucleosides, to the above nucleosides will also be investigated. It is also proposed that certain specific 3- ribosylpurines of the "cytidine type" be prepared. We also plan to initiate research into the synthesis of pyridazines, pyridazine nucleosides and certain bicyclic nucleosides prepared from pyridazine nucleosides. The above nucleosides will be designed as potential inhibitors or substrates of enzymes essential for nucleic acid synthesis and more specifically the pyrimidine biosynthetic pathway, e.g., thymidine phosphorylase, thymidine kinase, uridine kinase, uridine phosphorylase, orotidylate decarboxylase, pyrophosphorylase, etc. It is proposed to prepare not only the ribofuranosides but also the arabinofuranosides and possibly the 2-deoxyribofuranosides of the heterocyclic ring systems discussed above and initiate studies designed to establish the stability or degree of lability of the heterocyclic moiety of these nucleosides. The C13 NMR, ORD, CD and MCD of these nucleosides and related derivatives will be obtained on a routine basis and used in an effort to establish an insight into the relationship between the structure and conformation of certain nucleosides and their biological and chemotherapeutic activity. The nucleosides (and heterocyclic precursors) which will be prepared under this program will be submitted for evaluation as anticancer agents in the CCNSC screen and additional information will be obtained as a result of direct collaboration with several biochemists, pharmacologists, biologists, etc. at research institutes and universities.